Dermatology MCQ - Genetic Disorders - Xeroderma Pigmentosum

An 8-year-old child with a history of extreme, blistering sunburn from minimal sun exposure presents with numerous freckles on the face and a new, crusted lesion on the lower lip. On neurological examination, the child has high-frequency sensorineural hearing loss and diminished deep tendon reflexes. What is the underlying cellular defect and the most critical component of long-term management?

A. Defect in the complement membrane attack complex; management with prophylactic antibiotics.
B. Defect in melanin synthesis; management with strict vitamin D supplementation.
C. Defect in nucleotide excision repair (NER) pathway; management with absolute, rigorous sun protection and regular surveillance for skin and ocular cancers.
D. Defect in cytokine signaling for neutrophil migration; management with G-CSF injections.
E. Defect in hemoglobin synthesis; management with frequent blood transfusions.

Correct Answer: C. Defect in nucleotide excision repair (NER) pathway; management with absolute, rigorous sun protection and regular surveillance for skin and ocular cancers.

Answer and Explanation

The correct answer is C. This question describes the classic features of xeroderma pigmentosum (XP). The key clues are the severe photosensitivity (blistering sunburn with minimal exposure), the early development of freckles (solar lentigines) on sun-exposed skin, and the appearance of a pre-malignant or malignant skin lesion (the crusted lip lesion, likely actinic keratosis or squamous cell carcinoma) in childhood. The presence of neurological abnormalities (sensorineural hearing loss, areflexia) indicates XP with neurologic involvement (the DeSanctis-Cacchione variant or complementation groups with neurological features). The fundamental defect is in the nucleotide excision repair (NER) pathway, which repairs UV-induced DNA damage (cyclobutane pyrimidine dimers). Without NER, UV damage accumulates, leading to a >10,000-fold increased risk of skin cancers and ocular surface cancers. Therefore, lifelong, absolute sun protection and vigilant surveillance are the pillars of management.

Why the Other Options are Incorrect:

• A. Defect in the complement membrane attack complex: This describes a predisposition to Neisseria infections, not photosensitivity and cancer.

• B. Defect in melanin synthesis: This causes oculocutaneous albinism, which features photosensitivity and increased skin cancer risk due to lack of pigment, but it is not associated with defective DNA repair or the neurological abnormalities seen in XP.

• D. Defect in cytokine signaling for neutrophil migration: This describes leukocyte adhesion deficiency, leading to recurrent bacterial infections without pus formation.

• E. Defect in hemoglobin synthesis: This describes thalassemia or sickle cell disease, which do not cause photosensitivity.

Additional High-Yield Information for Exams:

• Genetics & Complementation Groups: Autosomal recessive. Caused by mutations in any of at least 8 genes (XPA through XPG, and XPV) involved in NER. XPA is often associated with severe neurological disease. XPV (variant form) has defects in a transfusion synthesis polymerase, not core NER, and typically lacks neurological symptoms.

• Clinical Features:

  • Skin: The classic progression is: 1) Severe sunburn in infancy, 2) Freckling on sun-exposed skin before age 2, 3) Development of actinic keratoses, 4) Skin cancers (BCC, SCC, melanoma) often before age 10.

  • Ocular: Photophobia, keratitis, corneal opacification, cancers of the conjunctiva and eyelids.

  • Neurological (in ~30%): Progressive neurodegeneration including sensorineural deafness, areflexia, ataxia, spasticity, and cognitive decline.

• Differential Diagnosis: Other photosensitivity disorders include:

  • Bloom Syndrome: Photosensitive rash, growth deficiency, cancer risk, but no freckling or neurological issues; caused by BLM helicase defect.

  • Cockayne Syndrome: Photosensitivity, growth failure, neurodegeneration, but no increased skin cancer risk; also an NER disorder but in the transcription-coupled repair sub-pathway.

  • Trichothiodystrophy: Photosensitivity, brittle hair, intellectual impairment, but also no increased skin cancer risk; caused by mutations in NER genes affecting transcription.

• Associated Conditions & Prognosis:

  • Cancer Risk: Median age of first skin cancer is 8 years. Without protection, most patients die of metastatic skin cancer or neurologic degeneration by young adulthood.

  • Prognosis: With extremely rigorous photoprotection, life expectancy can be significantly extended, and neurological progression may be slowed.

• Management & Rationale:

  • Rationale: To prevent UV-induced DNA damage and detect cancers at the earliest, most curable stage.

  • First-line/Obligatory Management: Absolute, lifelong photoprotection.

    • Environmental: Living in a UV-shielded environment (special window films, low-UV lighting).

    • Behavioral: Strict avoidance of daylight exposure. Going outside only after sunset.

    • Physical Protection: Full-coverage clothing, gloves, wide-brimmed hats, UV-blocking sunglasses.

    • Topical: Broad-spectrum, high-SPF sunscreen applied multiple times daily.

  • Surveillance: Frequent (every 3-6 month) total-body skin exams by a dermatologist, and regular ophthalmologic exams.

  • Treatment: Aggressive treatment of pre-cancers (actinic keratoses with cryotherapy, field therapy) and prompt excision of all skin cancers. Oral nicotinamide (a form of vitamin B3) has been shown to reduce the rate of new non-melanoma skin cancers in high-risk populations and may be used adjunctively.

  • Neurological: Supportive care. No treatment halts neurodegeneration.